The proposed research is a multidisciplinary, multicenter study to investigate the clinical, genetic and cardiologic aspects of the long QT syndrome (LQTS) - a predominantly hereditary disorder with episodic malignant ventricular arrhythmias and sudden death. The five-year research plan consists of: 1) a prospective population study to enroll and longitudinally follow 500 patients with LQTS and 1500 unaffected relatives in order to develop and validate widely applicable clinical criteria for stratifying the risk of life-threatening arrhythmic events in patients with this disorder; 2) a survey of a population of genetically deaf students (n=85) to identify additional families with the unique association of LQTS and congenital deafness in order to expand the data base for genetic studies in the recessive form of this disorder (Jervell and Lange-Nielsen Syndrome); 3) recording high quality pedigrees of selected LQTS families to better understand the inheritance of the dominant form of this disorder (Romano-Ward Syndrome); 4) genetic studies utilizing human leukocyte antigen (HLA) and other protein markers to investigate the gene locus for the autosomal dominant form of LQTS; and 5) non-invasive cardiologic studies (24-hour Holter recordings, treadmill exercise, valsalva maneuver and handgrip stress) in a select group of LQTS patients (n=30) and equal numbers of unaffected relatives and matched controls to determine if LQTS patients have a unique cardiovascular response or sensitivity to autonomic perturbations. These integrated populations, genetic and cardiac studies which we propose offer a substantal prospect of providing new insight into the nature of this hereditable arrhythmic disorder, of identifying individuals genetically and clinically at-risk for lethal arrhythmic events, of evaluating the efficacy of various treatment regimens and of understanding a fundamental mechanism in the genesis of one type of malignant ventricular arrhythmias that may have important implications for other cardiac disorders.